This invention relates to the use of certain pyrazolo[4,3-d]pyrimidin-7-ones, pyrazolo[3,4-d]pyrimidin-4-ones, quinazolin-4-ones, purin-6-ones and pyrido[3,2-d]pyrimidin-4-ones for the treatment of impotence.
Impotence can be defined literally as a lack of power, in the male, to copulate and may involve an inability to achieve penile erection or ejaculation, or both. More specifically, erectile impotence or dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse. Its prevalence is claimed to be between 2 and 7% of the human male population, increasing with age, up to 50 years, and between 18 and 75% between 55 and 80 years of age. In the USA alone, for example, it has been estimated that there are up to 10 million impotent males, with the majority suffering from problems of organic rather than of psychogenic origin.
Reports of well-controlled clinical trials in man are few and the efficacy of orally administered drugs is low. Although many different drugs have been shown to induce penile erection, they are only effective after direct injection into the penis, e.g. intraurethrally or intracavernosally (i.c.), and are not approved for erectile dysfunction. Current medical treatment is based on the i.c injection of vasoactive substances and good results have been claimed with phenoxybenzamine, phentolamine, papaverine and prostaglandin E1, either alone or in combination; however, pain, priapism and fibrosis of the penis are associated with the i.c. administration of some of these agents. Potassium channel openers (KCO) and vasoactive intestinal polypeptide (VIP) have also been shown to be active i.c., but cost and stability issues could limit development of the latter. An alternative to the i.c. route is the use of glyceryl trinitrate (GTN) patches applied to the penis, which has been shown to be effective but produces side-effects in both patient and partner.
As a general alternative to pharmacological intervention, a variety of penile prostheses has been used to assist achievement of an erection. The short term success rate is good, but problems with infection and ischaemia, especially in diabetic men, make this type of treatment a final option rather than first-line therapy.
The compounds of the invention are potent inhibitors of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDES) in contrast to their inhibition of cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cAMP PDEs). This selective enzyme inhibition leads to elevated cGMP levels which, in turn, provides the basis for the utilities already disclosed for the said compounds in WO-A-93/06104, WO-A-93/07149, WO-A-93/12095, WO-A-94/00453 and WO-A-94/05661 respectively, namely in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
Unexpectedly, it has now been found that these disclosed compounds are useful in the treatment of erectile dysfunction. Furthermore the compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration. Thus the present invention concerns the use of a compound of formula (I): 
wherein
R1 is methyl or ethyl;
R2 is ethyl or n-propyl; and
R3 and R4 are each independently H, or C1-C6 alkyl optionally substituted with C5-C7 cycloalkyl or with morpholino;
a compound of formula (II): 
wherein
R1 is C1-C6 alkyl;
R2 is H; methyl or ethyl;
R3 is C2-C4 alkyl;
R4 is H; C1-C4 alkyl optionally substituted with NR5R6, CN, CONR5R6 or CO2R7; C2-C4 alkenyl optionally substituted with CN, CONR5R6 or CO2R7; C2-C4 alkanoyl optionally substituted with NR5R6; SO2NR5R6; CONR5R6; CO2R7 or halo; R5 and R6 are each independently H or C1-C4 alkyl; or, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino, morpholino, 4-(NR8)-1-piperazinyl or 1-imidazolyl group wherein said group is optionally substituted with one or two C1-C4 alkyl groups;
R7 is H or C1-C4 alkyl; and
R8 is H; C1-C3 alkyl or (hydroxy) C2-C3 alkyl;
a compound of formula (III): 
wherein
R1 is H; C1-C4 alkyl; C1-C4 alkoxy or CONR5R6:
R2 is H or C1-C4 alkyl;
R3 is C2-C4 alkyl;
R4 is H; C2-C4 alkanoyl optionally substituted with NR7R8; (hydroxy)C2-C4 alkyl optionally substituted with NR7R8; CHxe2x95x90CHCO2R9;
CHxe2x95x90CHCONR7R8; CH2CH2CO2R9; CH2CH2CONR7R8;
SO2NR7R8; SO2NH (CH2)nNR7R8 or imidazolyl;
R5 and R6 are each independently H or C1-C4 alkyl;
R7 and R8 are each independently H or C1-C4 alkyl; or, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino, morpholino or 4-(NR10)-1-piperazinyl group wherein any of said groups is optionally substituted with CONR5R6;
R9 is H or C1-C4 alkyl;
R10 is H; C1-C3 alkyl or (hydroxy)C2-C3 alkyl; and
n is 2, 3 or 4;
with the proviso that R4 is not H when R1 is H, C1-C4 alkyl or C1-C4 alkoxy;
a compound of formula (IV): 
wherein
R1 is C1-C4 alkyl;
R2 is C2-C4 alkyl;
R3 is H or SO2NR4R5;
R4 and R5 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or 4-(NR6)-1-piperazinyl group; and
R6 is H or C1-C3 alkyl;
or a compound of formula (V): 
wherein
R1 is H; C1-C4 alkyl; CN or CONR4R5;
R2 is C2-C4 alkyl;
R3 is SO2NR6R7; NO2; NH2; NHCOR8; NHSO2R8 or N(SO2R8)2;
R4 and R5 are each independently selected from H and C1-C4 alkyl;
R6 and R7 are each independently selected from H and C1-C4 alkyl optionally substituted with CO2R9, OH, pyridyl, 5-isoxazolin-3-onyl, morpholino or 1-imidazolidin-2-onyl; or, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino, morpholino, 1-pyrazolyl or 4-(NR10)-1-piperazinyl group wherein any of said groups may optionally be substituted with one or two substituents selected from C1-C4 alkyl, CO2R9, NH2 and OH;
R8 is C1-C4 alkyl or pyridyl;
R9 is H or C1-C4 alkyl; and
R10 is H; C1-C4 alkyl or (hydroxy)C2-C3 alkyl;
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man.
In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms, and alkenyl and alkanoyl groups having four carbon atoms, may be straight chain or branched chain. Halo means fluoro, chloro, bromo or iodo.